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Photochemopreventive Effect of Pomegranate Fruit Extract on UVA‐mediated Activation of Cellular Pathways in Normal Human Epidermal Keratinocytes
Author(s) -
Syed Deeba N.,
Malik Arshi,
Hadi Naghma,
Sarfaraz Sami,
Afaq Farrukh,
Mukhtar Hasan
Publication year - 2006
Publication title -
photochemistry and photobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.818
H-Index - 131
eISSN - 1751-1097
pISSN - 0031-8655
DOI - 10.1562/2005-06-23-ra-589
Subject(s) - protein kinase b , phosphorylation , pi3k/akt/mtor pathway , kinase , photoaging , mapk/erk pathway , ribosomal s6 kinase , stat3 , chemistry , microbiology and biotechnology , signal transduction , reactive oxygen species , cancer research , biology , p70 s6 kinase 1 , genetics
UVA is the major portion (90–99%) of solar radiation reaching the surface of the earth and has been described to lead to formation of benign and malignant tumors. UVA‐mediated cellular damage occurs primarily through the release of reactive oxygen species and is responsible for im‐munosuppression, photodermatoses, photoaging and photocar‐cinogenesis. Pomegranate fruit extract (PFE) possesses strong antioxidant and anti‐inflammatory properties. Our recent studies have shown that PFE treatment of normal human epidermal keratinocytes (NHEK) inhibits UVB‐mediated activation of MAPK and NF‐κB pathways. Signal transducers and activators of transcription 3 (STATJ), Protein Kinase B/AKT and Map Kinases (MAPKs), which are activated by a variety of factors, modulate cell proliferation, apoptosis and other biological activities. The goal of this study was to determine whether PFE affords protection against UVA‐mediated activation of STAT3, AKT and extracellular signal‐regulated kinase (ERK1/2). Immunoblot analysis demonstrated that 4 J/ cm 2 of UVA exposure to NHEK led to an increase in phosphorylation of STAT3 at Tyr 705 , AKT at Ser 473 and ERK1/2. Pretreatment of NHEK with PFE (60–100 μg/mL) for 24 h before exposure to UVA resulted in a dose‐dependent inhibition of UVA‐mediated phosphorylation of STAT3 at Tyr 705 , AKT at Ser 473 and ERK1/2. mTOR, structurally related to PDK, is involved in the regulation of p70S6K, which in turn phosphorylates the S6 protein of the 40S ribosomal sub‐unit. We found that UVA radiation of NHEK resulted in the phosphorylation of mTOR at Thr 2448 and p70S6K at Thr 421 / Ser 424 . PFE pretreatment resulted in a dose‐dependent inhibition in the phosphorylation of mTOR at Thr 2448 and p70S6K at Thr 421 /Ser 424 . Our data further demonstrate that PFE pretreatment of NHEK resulted in significant inhibition of UVA exposure‐mediated increases in Ki‐67 and PCNA. PFE pretreatment of NHEK was found to increase the cell‐cycle arrest induced by UVA in the G1 phase of the cell cycle and the expression of Bax and Bad (proapoptotic proteins), with downregulation of Bcl‐X L expression (antiapoptotic protein). Our data suggest that PFE is an effective agent for ameliorating UVA‐mediated damages by modulating cellular pathways and merits further evaluation as a photochemopreventive agent.